The Mycobacterium tuberculosis Stress Response Factor SigH Is Required for Bacterial Burden as Well as Immunopathology in Primate Lungs

Mehra, Smriti; Golden, Nadia; Stuckey, Kerstan J.; Didier, Peter J.; Doyle, Lara A.; Russell‐Lodrigue, Kasi; Sugimoto, Chie; Hasegawa, Atsuhiko; Sivasubramani, Satheesh K.; Roy, Chad J.; Álvarez, Xavier; Kuroda, Marcelo J.; Blanchard, James; Lackner, Andrew A.; Kaushal, Deepak

doi:10.1093/infdis/jis102

Cited by 69 publications

(119 citation statements)

References 47 publications

(99 reference statements)

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“…The NHPs did not exhibit any clinical signs of TB, as evident from normal body temperatures and weights, chest x-rays, and serum levels of acute phase proteins (26). For A-TB, NHPs were infected with a high dose of Mtb CDC1551 via aerosol infection (~5,000 CFU) (58). Mtb exposure was confirmed by positive tuberculin skin test and PRIMAGAM, and the NHPs exhibited clinical signs of TB, as evident from body temperatures, weights, and chest x-rays (58).…”

Section: Methodsmentioning

confidence: 99%

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CXCR5+ T helper cells mediate protective immunity against tuberculosis

Slight¹,

Rangel-Moreno²,

Gopal³

et al. 2013

J. Clin. Invest.

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182

293

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One third of the world's population is infected with Mycobacterium tuberculosis (Mtb). Although most infected people remain asymptomatic, they have a 10% lifetime risk of developing active tuberculosis (TB). Thus, the current challenge is to identify immune parameters that distinguish individuals with latent TB from those with active TB. Using human and experimental models of Mtb infection, we demonstrated that organized ectopic lymphoid structures containing CXCR5 + T cells were present in Mtb-infected lungs. In addition, we found that in experimental Mtb infection models, the presence of CXCR5 + T cells within ectopic lymphoid structures was associated with immune control. Furthermore, in a mouse model of Mtb infection, we showed that activated CD4 + CXCR5 + T cells accumulated in Mtb-infected lungs and produced proinflammatory cytokines. Mice deficient in Cxcr5 had increased susceptibility to TB due to defective T cell localization within the lung parenchyma. We demonstrated that CXCR5 expression in T cells mediated correct T cell localization within TB granulomas, promoted efficient macrophage activation, protected against Mtb infection, and facilitated lymphoid follicle formation. These data demonstrate that CD4 + CXCR5 + T cells play a protective role in the immune response against TB and highlight their potential use for future TB vaccine design and therapy.

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Section: Methodsmentioning

confidence: 99%

“…For A-TB, NHPs were infected with a high dose of Mtb CDC1551 via aerosol infection (~5,000 CFU) (58). Mtb exposure was confirmed by positive tuberculin skin test and PRIMAGAM, and the NHPs exhibited clinical signs of TB, as evident from body temperatures, weights, and chest x-rays (58).…”

Section: Methodsmentioning

confidence: 99%

CXCR5+ T helper cells mediate protective immunity against tuberculosis

Slight¹,

Rangel-Moreno²,

Gopal³

et al. 2013

J. Clin. Invest.

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182

293

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“…Expression of the M. tuberculosis factors H , E , and B can be triggered by either H or E (268,269). A growing body of literature indicates that these sigma factors are induced in response to several different in vitro conditions mimicking in vivo stresses faced by the pathogen during the various stages of infection and disease (263)(264)(265)(266)(267)270).…”

Section: The Stringent Responsementioning

confidence: 99%

“…tuberculosis E is induced upon uptake by macrophages and upon treatment with hydrogen peroxide and SDS, leading to activation of 23 genes, including sigB, mprA, mprB, and four other transcription factor genes (257). An M. tuberculosis sigH deletion (⌬sigH) mutant showed reduced survival and pathology in the lungs of rhesus macaques and reduced lung inflammation in mice (265,267,270).…”

Section: The Stringent Responsementioning

confidence: 99%

Latent Tuberculosis Infection: Myths, Models, and Molecular Mechanisms

Dutta

Karakousis

2014

Microbiol Mol Biol Rev

191

174

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SUMMARY The aim of this review is to present the current state of knowledge on human latent tuberculosis infection (LTBI) based on clinical studies and observations, as well as experimental in vitro and animal models. Several key terms are defined, including “latency,” “persistence,” “dormancy,” and “antibiotic tolerance.” Dogmas prevalent in the field are critically examined based on available clinical and experimental data, including the long-held beliefs that infection is either latent or active, that LTBI represents a small population of nonreplicating, “dormant” bacilli, and that caseous granulomas are the haven for LTBI. The role of host factors, such as CD4 + and CD8 + T cells, T regulatory cells, tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ), in controlling TB infection is discussed. We also highlight microbial regulatory and metabolic pathways implicated in bacillary growth restriction and antibiotic tolerance under various physiologically relevant conditions. Finally, we pose several clinically important questions, which remain unanswered and will serve to stimulate future research on LTBI.

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“…Lung tissue was fixed for hematoxylin-eosin histology and confocal microscopy (18)(19)(20)(21)(22). Ten images of each slide were used for analysis (Inform; PerkinElmer, Waltham, MA).…”

Section: Staining Procedures Histopathology and Microscopymentioning

confidence: 99%

DosS Is Required for the Complete Virulence of Mycobacterium tuberculosis in Mice with Classical Granulomatous Lesions

Gautam¹,

McGillivray²,

Mehra

et al. 2015

Am J Respir Cell Mol Biol

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Mycobacterium tuberculosis (Mtb) must counter hypoxia within granulomas to persist. DosR, in concert with sensor kinases DosS and DosT, regulates the response to hypoxia. Yet Mtb lacking functional DosR colonize the lungs of C57Bl/6 mice, presumably owing to the lack of organized lesions with sufficient hypoxia in that model. We compared the phenotype of the D-dosR, D-dosS, and D-dosT mutants to Mtb using C3HeB/FeJ mice, an alternate mouse model where lesions develop hypoxia. C3HeB/FeJ mice were infected via aerosol. The progression of infection was analyzed by tissue bacterial burden and histopathology. A measure of the comparative global immune responses was also analyzed. Although D-dosR and D-dosT grew comparably to wild-type Mtb, D-dosS exhibited a significant defect in bacterial burden and pathology in vivo, accompanied by ablated proinflammatory response. D-dosS retained the ability to induce DosR. The D-dosS mutant was also attenuated in murine macrophages ex vivo, with evidence of reduced expression of the proinflammatory signature. Our results show that DosS, but not DosR and DosT, is required by Mtb to survive in C3HeB/FeJ mice.The attenuation of D-dosS is not due to its inability to induce the DosR regulon, nor is it a result of the accumulation of hypoxia. That the in vivo growth restriction of D-dosS could be mimicked ex vivo suggested sensitivity to macrophage oxidative burst. Anoxic caseous centers within tuberculosis lesions eventually progress to cavities. Our results provide greater insight into the molecular mechanisms of Mtb persistence within host lungs.Keywords: Mycobacterium tuberculosis; hypoxia; response regulator; sensor kinase; latency Clinical RelevanceOur research indicates that the C3HeB/FeJ mouse model is appropriate for the study of Mycobacterium tuberculosis pathogenesis because it reveals attenuation in the D-dosS mutation. It appears that this attenuation is not the result of hypoxia in lung granulomas.

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The Mycobacterium tuberculosis Stress Response Factor SigH Is Required for Bacterial Burden as Well as Immunopathology in Primate Lungs

Abstract: The Mtb:Δ-sigH mutant is completely attenuated for bacterial burden as well as immunopathology in NHPs. SigH and its regulon are required for complete virulence in primates. Further studies are needed to identify the molecular mechanism of this attenuation.

Cited by 69 publications

References 47 publications

CXCR5+ T helper cells mediate protective immunity against tuberculosis

CXCR5+ T helper cells mediate protective immunity against tuberculosis

Latent Tuberculosis Infection: Myths, Models, and Molecular Mechanisms

DosS Is Required for the Complete Virulence of Mycobacterium tuberculosis in Mice with Classical Granulomatous Lesions

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